Is ATL3 p.Ser258= (c.774C>T) pathogenic?

ATL3 p.Ser258= (c.774C>T) is classified Conflicting classifications of pathogenicity in ATL3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-04-16). Ultra-rare (popmax 0.0329%, mid); Associated with neuropathy, hereditary sensory, type 1F.

What condition is associated with ATL3 p.Ser258= (c.774C>T)?

ATL3 p.Ser258= (c.774C>T) is associated with neuropathy, hereditary sensory, type 1F (ClinVar).

How common is ATL3 p.Ser258= (c.774C>T) in the general population?

ATL3 p.Ser258= (c.774C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

ATL3 p.Ser258=

Q: How is Hereditary sensory and autonomic neuropathy type 1 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.774C>T · rs61745653 · VCV2851199

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

neuropathy, hereditary sensory, type 1F

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.22	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -0.12	GERP -4.3, phastCons 0.06
Overall
CADD	12.93	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,080 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00397% 64/1,612,406 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,040
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,793
Admixed American	0.00669%	14,953
Remaining individualsnot grpmax-eligible	0.0048%	20,812
European (non-Finnish)	0.00416%	24,066
African / African-American	0.00401%	24,949
South Asian	0.0011%	90,676

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ATL3
Protein: p.Ser258=
Coding: c.774C>T
MANE Select: NM_015459
dbSNP: rs61745653
Type: single nucleotide variant
Location: chr11:63643433 (GRCh38)
Gene constraint: LOEUF 0.891 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.30 · 2 PDB
Residue 258: a β-strand; the gb1/rhd3-type g domain

Full ATL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuropathy, hereditary sensory, type 1F — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary sensory and autonomic neuropathy type 1 (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

ATL3 c.1035+1G>A Uncertain significance ★★ same condition
ATL3 c.46+1G>A Uncertain significance ★★ same condition
ATL3 c.619-4A>G Uncertain significance ★★ same condition
ATL3 c.711+1G>T Uncertain significance ★★ same condition
ATL3 c.850+5G>A Uncertain significance ★★ same condition
ATL3 p.Ala457Val Uncertain significance ★★ ⚠ same condition
ATL3 p.Ala508Thr Uncertain significance ★★ ⚠ same condition
ATL3 p.Ala540Ser Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/atl3-p-ser258 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown